Amit Kakkar, PGY1Georgetown University Hospital

Dept of Medicine

January 25, 2008

Ground Glass Changes in Transplanted Livers: Another

Toxic Effect of Calcineurin Inhibitors?

Background Liver transplantation started in 1950’s1st human OLT done in 1963; survival still poor1st anti-rejection meds: steroids and

azathioprine graft survival = 30%With introduction calcineurin inhibitors

(cyclosporine and tacrolimus), 1yr graft survival >90%

Rejection – multistep process including alloantigen recognition, lymphocyte activation, clonal expansion, and inflammation meds are able to block each step in the pathway

Mechanism of CIN

Fantini et alNature Clinical Practice Gastroenterology & Hepatology (2006) 3, 633-644

Cyclosporine vs. Tacrolimus (FK506)Landmark Trial occurred in 1994 by the US

Multicenter FK506 Liver study group with results published in N. England Journal large, multicenter, randomized open label studyOutcomes: 1) Reaffirmed that rejection was an

important cause of graft loss and death2) Survival between tacrolimus and

cyclosporine were similar, but less significantly less incidence of steroid resistant rejection with tacrolimus

3) FK506 assoc with excess adverse effects including neurotoxicity and nephrotoxicity

Dosage/MonitoringTherapeutic Trough

Range: 5-10ng/ml. May increase

trough goal if OLT 2nd to autoimmune hepatitis

OLT patients likely on extensive drug regimens

Masuda & Inuchi. Pharmacology &Therapeutics.

Mechanisms of Drug Induced Liver Injury

The Ground Glass Phenomenon

Typically, ground glass changes seen with HBV

EM ground glass predominantly glycogen

Prior studies were not limited to OLT pts, but med profile suggested immunosuppressives

Proposed mechanism: altered glycogen metabolism 2nd polypharmacotherpy

Adaptive change vs. sign of hepatotoxicity

Wisell et al. Glycogen Am J of Surg Pathology (2006) vol 30, 9

Histology

Ground Glass 2nd to CIN?My research:

Retrospective chart review of OLT patients @GUH from 2004-2007, with +ground glass changes on liver bx

Record demographics, hepatic panel, time to bx, and medication regimen 1 and 3months prior to bx, adverse events

Record CIN levels at 1 and 3months prior to bx

Exclusion criteria: cyanamide tx, +HBV recurrence, hx glycogen storage disease

ResultsTotal 8 cases identified

o -1 female, 7 maleo Age: 31 -72o Tx indication: 1 PSC, 1 AIH, 3HBV/HCC, 3HCV/HCCo Bx indication: increased LFTs

Common Medication: Tacrolimus, PPIMean: AST 151, ALT 224, ALP 241, TP 3.4, Alb 6,

tbili 1.2, GGTP 413Mean: days to bx 153 Fk506 levels: 1mo 10.4, 3mo 11.2, <1wk to bx

10.73cases with repeat bx – 2 cases no longer with

histologic changes

Further InvestigationAdaptive change vs. sign of hepatotoxicityReanalysis of repeat bx that were negative

for similar changesMedication reconciliation –inhibitors?

inducers? drug levelsRole of mycophenolate mofetil (MMF) – 4

out of the cases were concomittantly on MMF

Analysis of bx by EM

AcknowledgementsDr. K. Shetty, Dept of Hepatology,

GastroenterologyStaff at the Transplant Institute and

International Center for Liver DiseasesDr. B. Kallakury, Dept of Pathology

References A comparison of tacrolimus (FK 506) and cyclosporine for

immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 1994; 331:1110

Fantini, Christoph Becker, Ralf Kiesslich and Markus F Neurath. Drug Insight: novel small molecules and drugs for immunosuppression Nature Clinical Practice Gastroenterology & Hepatology (2006) 3, 633-644.

Hasenbein et al. Long term evaluation of cyclosporine and tacrolimus based immunosuppression in pediatric liver transplantation. Pediatric Transplantation. (2006) 10, 938-942.

Larson, Ann. Drugs and the Liver: Patterns of Hepatotoxicity. www.uptodate.com.

Lefkowitch et al. Ground-Glass, Polyglucosan Like Hepatocellular Inclusions: A “New” diagnostic Entity. Gastroenterology (2006); 131: 713-718.

Masuda and Inui. An uptodate review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacology and Therapeutics. 112 (2006). 184-196.

Wisell et al. Glycogen Psuedoground Glass Change in Hepatocytes. Am J of Surg Pathology (2006) vol 30, 9, 1085-1089.